* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download In vivo imaging of dopamine and serotonin release Udo de
Survey
Document related concepts
Plateau principle wikipedia , lookup
5-HT3 antagonist wikipedia , lookup
Cannabinoid receptor antagonist wikipedia , lookup
Toxicodynamics wikipedia , lookup
Drug design wikipedia , lookup
Discovery and development of angiotensin receptor blockers wikipedia , lookup
Nicotinic agonist wikipedia , lookup
Theralizumab wikipedia , lookup
Discovery and development of antiandrogens wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Methylphenidate wikipedia , lookup
NK1 receptor antagonist wikipedia , lookup
Transcript
University of Groningen In vivo imaging of dopamine and serotonin release Udo de Haes, Joanna Irene IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2005 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Udo de Haes, J. I. (2005). In vivo imaging of dopamine and serotonin release: response to psychopharmacological challenges s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 18-06-2017 CHAPTER 5 ASSESSMENT OF METHYLPHENIDATEINDUCED CHANGES IN BINDING OF CONTINUOUSLY INFUSED 11 [ C]-RACLOPRIDE IN HEALTHY HUMAN SUBJECTS: CORRELATION WITH SUBJECTIVE EFFECTS 1 2,3 4 2,5 4 J. I. Udo de Haes , R. Kortekaas , A. Van Waarde , R.P. Maguire , J.Pruim , 1 J. A. den Boer 1 Department of Biological Psychiatry, University Medical Center Groningen, 2Department of Neurology, University Medical Center Groningen, 3Department of Anatomy and Embryology, University Medical Center Groningen, 4PET center, University Medical Center Groningen, 5Pfizer Global Research and Development, USA Psychopharmacology, in press 111 [11C]-Raclopride binding in human subjects Abstract The dopaminergic system has been implicated in the pathogenesis and treatment of a variety of neuropsychiatric disorders. It has been shown that information on endogenous dopamine (DA) release can be obtained noninvasively, by combining positron emission tomography (PET) with a dopaminergic challenge. This approach is based on the assumption that an injected radiolabeled ligand competes with the neurotransmitter for the same receptor. Increases in DA release will therefore result in a decreased binding of the radioligand. We investigated the effect of the DA reuptake blocker methylphenidate (MP) (0.25 mg/kg i.v) on the binding of the D2 receptor ligand [11C]-raclopride (RAC) in 6 healthy volunteers. RAC was administered as a bolus followed by constant infusion and subjective effects were assessed using verbal rating scales. Control scans without MP administration, showed that the mean RAC binding reached stable values approximately 30 minutes after start of the infusion. MP administration induced a 24% decrease in RAC binding in the total striatum. Significant correlations were found between the MP-induced change in euphoria and percent change in binding potential (ΔBP) in the dorsal striatum and between baseline anxiety and ΔBP in the dorsal and middle striatum. We also found a significant negative correlation between baseline BP in the dorsal striatum and change in euphoria. Our results comply with previous findings, indicating the feasibility of the bolus infusion design combined with a relatively low MP dose to study dopaminergic (dys)function. 112 Chapter 5 Introduction The dopaminergic system has been implicated in the pathogenesis and treatment of a variety of neurological and psychiatric disorders such as schizophrenia, Parkinson’s disease, depression and addiction (Kapur and Mamo 2003; Leenders 2002; Naranjo et al. 2001; Volkow et al. 2002a). The involvement of dopamine (DA) in these disorders may be related to its function in reward processing (Kapur 2003; Kunig et al. 2000; Schmidt et al. 2001). However, the exact role of DA in these processes is not completely known yet. In order to study the (dys)function of the dopaminergic system, it is important to quantify changes in DA levels in the living brain. Over the last decade, it has been shown that information on endogenous DA release can be obtained noninvasively, by using positron emission tomography (PET) or single-photon emission computed tomography (SPECT). This approach is based on the assumption that an injected radiolabeled ligand competes with the endogenous neurotransmitter for the same receptor. Increases in DA release will result in a decreased binding of the radioligand and vice versa (Dewey et al. 1993; Laruelle 2000). The exact mechanism for these changes in receptor availability is not known. The changes may be a result of true competition between DA and the injected ligand, but may also be due to DA-induced internalization of the receptor (Sun et al. 2003). Nevertheless, it is generally assumed that the changes in radioligand binding can be used as a measure for the alterations in neurotransmitter release (Laruelle 2000). Using this method, correlations between DA function and behavioral or physiological scores have been found, providing information on the possible role of this neurotransmitter in pathological or physiological processes (Drevets et al. 2001; Laruelle et al. 1995; Leyton et al. 2002; Martinez et al. 2003; Pruessner et al. 2004; Volkow et al. 1994, 1999a, 2003). Previous studies that investigated changes in DA levels, have primarily assessed changes in striatal binding, using D2 receptor antagonists such as [11C]-raclopride (RAC) or [123I]-IBZM. In most studies a paired bolus protocol was used, with two separate scans: a dopaminergic challenge is 113 [11C]-Raclopride binding in human subjects administered during one of the scans while the other scan serves as a control. Alternatively, the ligand may be administered as a bolus followed by a constant infusion, leading to sustained equilibrium of radioligand levels in blood and brain (Carson 2000). A challenge can then be administered during the equilibrium period, enabling measurement of baseline and druginduced changes in ligand binding in the same experiment. During equilibrium, there is no net transfer of the radioligand across the blood-brain barrier, thereby minimizing possible effects of changes in drug-induced blood flow on ligand binding (Laruelle 2000). This aspect is an important advantage of the bolus with infusion paradigm, as compared to the double bolus protocols. Previous studies using RAC as a bolus followed by infusion have used amphetamine (AMPH) to assess pharmacologically-induced changes in dopaminergic transmission (Breier et al. 1997; Carson et al. 1997; Martinez et al. 2003; Tsukada et al. 2002). Since AMPH is not a registered drug in the Netherlands, we aimed to investigate the effect of the DA reuptake blocker methylphenidate (MP). Microdialysis studies have shown that both compounds induce large increases in DA levels (Breier et al. 1997; Hernandez et al. 1987; Hurd and Ungerstedt 1989; Kuczenski and Segal 1997) which resulted in 15-25% reductions in RAC binding in human subjects (Breier et al. 1997; Drevets et al. 2001; Martinez et al. 2003; Piccini et al. 2003; Volkow et al. 1994). The effect of MP on RAC binding has only been investigated using the double bolus method. Using this method, Volkow et al. (1999a) studied the effect of a wide range of MP doses and found significant changes in specific binding after intravenous doses of 0,25 mg/kg and 0,5 mg/kg. The effect of MP on RAC binding has not yet been investigated using a bolus with constant infusion protocol. In our study we used this protocol to investigate the effect of MP in healthy volunteers. In future studies we intend to use this method to study the dopaminergic system in psychiatric patients. We used a MP dose of 0.25 mg/kg, i.v., since in previous studies comparable doses were used in psychiatric patients (Janowsky and Davis 1976; Joyce et al. 1986). In order to check the equilibrium state of the ligand, we also investigated the protocol without MP administration. We assessed the subjective state of the subject before and after MP administration, since previous studies reported correlations 114 Chapter 5 between subjective effects and changes in ligand binding (Drevets et al. 2001; Laruelle et al. 1995; Leyton et al. 2002; Martinez et al. 2003; Volkow et al. 1994, 1999a). Finally, studies using AMPH have found a larger effect on ligand binding in more ventral compared to dorsal regions of the striatum. Therefore, we studied the effect of MP in different striatal regions. The aim of our study was to investigate if the results from the combined use of a relatively low dose of MP with a RAC constant infusion protocol comply with results from previous studies that used different dopaminergic challenges or double bolus injections. Materials and Methods Subjects Six healthy volunteers participated in the study (5 male, 1 female, mean age 24 year, range 18-32 years). All subjects gave written informed consent after written and oral explanation of the study. Suitability to participate in the study was determined by an independent physician after a medical examination including an ECG and routine blood hematology and biochemistry tests. Exclusion criteria were current or past psychiatric, neurological or other diseases that could interfere with the study, dependence on any substance other than nicotine or caffeine and exposure to psychoactive drugs during the past 3 months. The study was approved by the Medical Ethics Committee of the University Medical Center Groningen (UMCG). [11C]-raclopride synthesis The tracer [11C]-raclopride was prepared from [11C]-methyl iodide as previously described by Ehrin et al. (1987). It was dissolved in a volume of 20 mL sterile saline, and taken to the subject in the PET scanner. The specific radioactivity was >10.000 GBq/mmol at the time of injection. 115 [11C]-Raclopride binding in human subjects PET scan protocol The subjects were instructed to refrain from alcohol and caffeine containing products during 24 hours prior to each scan. Before the start of the PET scan an intravenous catheter was inserted in each arm for blood sampling and MP injection and for ligand administration. The volunteers were positioned in the camera and their heads were fixed using a head restraint. The subjects were scanned in 3D acquisition mode using a Siemens ECAT Exact HR+ camera, giving 63 slices with a center to center distance of 2.425 mm. During the scans, RAC was administered as a fast bolus (1 minute) followed by a constant infusion over 90 minutes with a bolus to infusion rate ratio (Kbol) of 100 minutes. The mean (± SD) activity at the start of the experiment was 220 (± 99) MBq). Thirty-six consecutive frames were acquired with a duration of 2.5 minutes. Each subject was scanned twice. One of the scans served as a control scan to check the equilibrium state of the ligand. During the other scan MP 0.25 mg/kg was injected intravenously over 1 minute, at 40 minutes after start of the RAC infusion. The two scans were performed in random order separated by 2 -7 months. During both scans plasma samples were taken for metabolite analysis at 5, 30, 60 and 90 minutes after the start of the RAC infusion. During the MP scan, subjective and behavioral effects were evaluated using a verbal analog rating scale, at 10 minutes before and 10 minutes after MP injection. The subjects were asked to respond to the following descriptors, using a whole number between 0 (no effects) and 10 (maximal effects): Euphoria, anxiety, happiness, sexual desire, desire for MP, alertness, annoyance, distrust, loss of control, restlessness, depression (Volkow et al. 1999a,b; Wang et al. 1997). Blood pressure, heart rate and ECG were continuously monitored during the MP scans. Metabolite analysis Plasma samples from only five subjects were analyzed due to sampling problems in one of the volunteers. After centrifugation with acetonitrile, the liquid phase of the samples was injected into the HPLC system, which contained a 300 x 7.9 mm μBondapak C18 semi-preparative column. The column was eluted with a mixture of acetonitrile / water / 85% phosphoric acid (500:500:1) at a flow rate of 2 ml/min. Fractions of the eluate were collected at 0.5 min intervals and radioactivity in the fractions was 116 Chapter 5 determined using a gamma counter. The relative contributions of parent and metabolites were calculated. Image analysis Attenuation correction was performed by drawing ellipses on the brain images, assuming uniform attenuation. Statistical Parametric Mapping (SPM) 99 was used for spatial normalization of the RAC image. A summation of the first 10 RAC frames was normalized to the SPM [15O]-H2O template, giving 68 horizontal planes. The normalization parameters were thereafter used to normalize the other frames of the RAC scan. A predetermined standard region of interest (ROI) template localized in stereotactic MNI space was applied to determine the ROIs including left and right dorsal, middle and ventral caudate nucleus, dorsal and ventral putamen, cerebellum and occipital cortex. For further analyses we defined the following three striatal subregions: dorsal (mean of six horizontal slices containing the dorsal caudate and putamen), middle (mean of 4 horizontal slices containing the middle caudate and ventral putamen) and ventral (mean of 3 horizontal slices containing the ventral caudate, including the nucleus accumbens). An activity threshold of 30% was used to extract stable peak values from the ROIs (Rottenberg et al. 1991). Time activity curves from striatal and occipital regions were obtained. Estimates of the mean BP were calculated with (Ct-Cref)/Cref (Ito et al. 1998), were Ct is the mean activity over a time interval (T) in the region of interest and Cref is the mean activity over T in a reference region. Intervals were T1 (32.5-40 minutes) and T2 (65-80 minutes). During T1, RAC binding was relatively stable, as assessed by visual inspection of the time-activity curves. T2 was chosen as a compromise between effect size and signal to noise ratio. In our study we selected the occipital cortex as reference region since the activity in the cerebellum was relatively noisy, probably due to low injected activity. The density of D2 receptors is negligible in the occipital region compared to the striatum (Camps et al. 1989; Lidow et al. 1989), and has been used before as a reference region for D2 binding (Booij et al. 1997; Kegeles et al. 1999; Laruelle et al. 1995; Laruelle et al. 1997). The baseline subjective scores and the scores after MP minus baseline score were used as outcome measures for the behavioral effects. 117 [11C]-Raclopride binding in human subjects Sttistical analysis Differences between BP(T1) and BP(T2) were calculated for the control and MP scans, using a paired t-test. Percent change in BP (ΔBP) was calculated as follows: (BP(T2) - BP(T1) / BP(T1)) x 100. ΔBP was assessed for the control and MP scans for the total striatum and the striatal subregions (dorsal, middle and central) and differences in ΔBP between the control and MP condition were calculated using paired t-tests. The effect of MP on the subjective scores was assessed using paired t-test. Pearson product moment correlations were calculated between the behavioral changes and ΔBP (difference between ΔBP in the control and MP condition) in the striatal subregions. Based on previous studies we investigated the following correlations: ΔBP with MP-induced change in euphoria, anxiety at baseline with ΔBP and baseline BP (mean of control and MP scans) with change in euphoria (Drevets et al. 2001, Laruelle et al. 1995; Martinez et al. 2003, Volkow et al. 1994, 1999a,b, 2002b). The effect of MP on blood pressure and heart rate was tested with a paired t-test. The four values measured during an interval of 30 minutes before start of the PET scan were compared to the six values obtained between four to eighteen minutes after MP administration which was the time period when peak effects occurred. Drugs Methylphenidate was obtained from Fagron farma BV, the Netherlands and infusions were prepared and provided by the pharmacy of the UMCG. Results Metabolite analysis As in previous studies, raclopride metabolism was not significantly altered by MP (Figure 1) (Drevets et al. 2001; Martinez et al. 2003; Volkow et al. 1994). 118 Chapter 5 % [11C]raclopride in plasma Control Methylphenidate 100.0 80.0 60.0 40.0 20.0 0.0 5 30 60 90 Time after start of the infusion (min) 11 Figure 1: Percent unchanged [ C]raclopride in plasma at 5, 30, 60 and 90 11 minutes after start of the [ C]raclopride infusion in control and methylphenidate scans. Methylphenidate (0.25 mg/kg) was injected at 40 minutes after start of the infusion. Cardiovascular measurements MP significantly increased heart rate (p < 0.001) and systolic (p < 0.001) and diastolic blood pressure (p < 0.001). Increases ranged from 40-70% (heart rate), 20-40% (systolic blood pressure) and 20-30% (diastolic blood pressure). The effects on heart rate and blood pressure are in agreement with results from previous studies (Volkow et al. 2003). No significant changes were observed in the ECG, apart from the increases in heart rate. PET measurements Mean time-activity curves for the control scans and MP scans (total binding and ratio to the occipital cortex) are shown in fig 2. In the control condition, the mean RAC BP reached relatively stable values approximately 30 119 [11C]-Raclopride binding in human subjects minutes after the start of the infusion. MP administration induced a decrease in RAC binding in the striatum, whereas binding in the occipital cortex was not affected. A paired t-test showed a significant difference between striatal BP before (BP(T1)) and after (BP(T2)) MP administration (p< 0.001) whereas in the control condition no difference was found between BP(T1) and BP(T2) (p = 0.470). Mean ΔBP in the total striatum after MP injection was -24% (range -14 to -40%), whereas the mean ΔBP in the control condition was 0% (range +33 to -21%). Since not all individual time activity curves in the control situation were in equilibrium, we used the difference in ΔBP between the MP and control scans, for further analyses. The mean difference in ΔBP between the MP and control condition was -24% (range 0 to -48%). The difference in ΔBP between the control and MP condition was larger in the ventral striatum (43%, range +19 to -128%) compared to the middle (-27%, range -1 to -46%) and dorsal striatum (-13%, range -5 to -18%). A paired t-test showed a significant difference in ΔBP between the control and MP condition in whole striatum (p = 0.029), the dorsal (p = 0.001) and middle striatum (p = 0.026) but not in the ventral striatum (p = 0.122). Subjective effects MP significantly increased the scores for euphoria (p = 0.01), restlessness (p = 0.003), and desire for MP (p < 0.001). The behavioral response differed between subjects. Most subjects described the experience as pleasurable, only one of the subjects described the effect as partly unpleasurable. Significant correlations were found between change in euphoria and ΔBP in the dorsal striatum (p = 0.006) and between baseline anxiety and ΔBP in the dorsal (p = 0.037) and middle striatum (p = 0.005). We found a significant negative correlation between baseline BP in the dorsal striatum and change in euphoria (p = 0.037) (Figure 3). 120 Chapter 5 Striatum CON Striatum MP Occipital CON Occipital MP Bq/cc/dose 20 15 MP 10 5 0 0 10 20 30 40 50 60 70 80 90 100 Time (min) A Striatum Mean CON Mean MP MP Mean [11C]Raclopride binding ratio 2.5 2 1.5 1 0.5 0 0 B 10 20 30 40 50 60 70 80 90 100 Time (min) Figure 2: A: Mean time-activity curves of total RAC uptake for the control and methylphenidate scans. B: Mean (± SD) time-activity curves of the binding ratio ((Ct-Cref)/Cref) to the occipital cortex for the control scans and methylphenidate scans. CON: control. MP: methylphenidate. 121 Change in euphoria [11C]-Raclopride binding in human subjects 6 5 4 3 2 1 0 R2 = 0.8772 0 5 10 15 20 % decrease in BP (dorsal striatum) A Baseline anxiety 3 2 1 0 R2 = 0.7037 -1 0 Change in euphoria 10 15 20 % decrease in BP (dorsal striatum) B 6 5 4 3 R2 = 0.7871 2 1 0 1 C 5 1.2 1.4 1.6 1.8 2 Baseline BP (dorsal striatum) Figure 3: Correlations between % decrease in BP (MP-CON) and change in euphoria (A), % decrease in BP (MP-CON) and baseline anxiety (B) and between baseline BP and change in euphoria (C). 122 Chapter 5 Discussion In the present study we investigated the effect of a relatively low dose of MP on RAC binding. This is the first study that investigated the effect of MP using a bolus with infusion protocol. The mean RAC BP reached relatively stable values approximately 30 minutes after the start of the infusion. Immediately after MP administration, a clear reduction in striatal RAC binding was seen, suggesting increased DA levels. Previous human studies have shown that MP or AMPH-induced changes in RAC binding usually ranged between 15-25%, in double bolus or bolus with infusion studies (Breier et al. 1997; Drevets et al. 2001; Martinez et al. 2003; Piccini et al. 2003; Volkow et al. 1994). These studies also reported large differences between the individual subjects. Using a double bolus design, Volkow et al. (1999a) showed that MP (0.25 mg/kg) induced a change in RAC binding that ranged from approximately +5 to -30%. With respect to the method of ligand administration, Carson et al. (1997) reported a larger drug-induced change in RAC binding using a paired bolus design compared to the bolus with infusion method. Although the difference was not significant, they suggest that the methods may differ in sensitivity due to differences in timing of the drug with respect to tracer delivery. However, in another study, the reduction in drug-induced BP did not differ between the double bolus or constant infusion method (Marenco et al. 2004). In our bolus with infusion study, the MP-induced changes in BP were comparable to the changes in the double bolus study by Volkow et al. (1999a). In our and previous studies, correlations were found between changes in DA release and subjective effects. DA release, especially in the striatum, has been implicated in the processing of rewarding or reinforcing effects of certain stimuli (Ikemoto and Panksepp 1999; McClure et al. 2004; Spanagel and Weiss 1999; Ungless 2004; Wise 2004). Data indicate that DA is released both after unexpected rewards, during expectation of a reward and desire for a reward and also after novel stimuli (Berridge and Robinson 1998; De la Fuente Fernandez et al. 2002; Leyton et al. 2002; Schultz 1998). DA increases have been found both in the dorsal and in the ventral striatum. The DA release in the different subdivisions in the striatum may depend on the nature of the reward and the behavioral response. In our 123 [11C]-Raclopride binding in human subjects study, we have found a correlation between the MP-induced change in euphoria and BP change in the dorsal striatum. Previous studies using AMPH have found correlations between drug-induced euphoria and BP changes in the ventral but not the dorsal striatum (Drevets et al. 2001; Martinez et al. 2003). In contrast, Leyton et al. (2002) found that AMPHinduced BP change in the ventral striatum correlated more with “drug wanting” than with mood elevation. Moreover, studies with placebo injections in Parkinson’s patients showed correlations of placebo-induced DA release in the ventral striatum during expectation of the reward (De la Fuente Fernandez et al. 2002) and dorsal striatum during experience of the reward (clinical improvement) (De la Fuente Fernandez et al. 2001). In addition, Small et al. (2003) found that BP change in the dorsal striatum correlated with meal pleasantness and monetary reward-induced DA release has been found in the medial caudate but not in ventral striatum (Zald et al. 2004). Pleasurable experience after smoking was associated with increased DA release in dorsal striatum (Barrett et al. 2004). Previous studies using MP showed that drug-induced euphoria correlated with DA increase in the whole striatum, which according to the authors consisted mainly of the dorsal striatum (Volkow et al. 1999a). The correlation between MP-induced changes in euphoria and BP changes in the dorsal striatum in our study, therefore agrees with the findings from previous studies with MP and studies using non-drug challenges. In our study, the reduction in RAC was larger in the ventral striatum compared to the dorsal striatum, although not significant. The lack of significance may be due to the high variability in this region. Some previous studies using AMPH have shown larger changes in the ventral striatum (Drevets et al. 2001; Leyton et al. 2002; Martinez et al. 2003) which is in agreement with animal studies that have shown that drugs of abuse preferentially increase DA release in the nucleus accumbens (Di Chiara and Imperato 1988). It is however not known if this also applies to MP. We found significant correlations between MP-induced BP changes and baseline anxiety. Since MP only blocks reuptake, it is dependent on the extent of physiologically released DA, and therefore on the subjective state of the subject during the experiment (Volkow et al. 1994). Volkow et al. 124 Chapter 5 (1994) has also found correlations between baseline anxiety and MPinduced changes in BP. They postulate that higher anxiety scores may reflect a higher responsiveness of the subjects to novel stimuli and/or unfamiliar situations, which could be linked with a more responsive DA system. In agreement with these findings are studies which show an effect of stress and cortisol on MP- and AMPH-induced increases in DA levels (Marsteller et al. 2002; Oswald et al. 2005). In addition, in our study a significant negative correlation between baseline BP and change in euphoria was seen. This is also in agreement with studies by Volkow et al. (1999b, 2002b). As Volkow et al. suggest, it is possible that in subjects with a high D2 receptor density, a smaller dose of MP may have been perceived as pleasant (Volkow et al. 2002b). The low D2 density could have been caused by high baseline DA levels. However, Volkow et al. (2002b) showed that the measurements were stable over different experiments suggesting that they were not influenced by differences in DA concentration which, in contrast to D2 density, may fluctuate rapidly between measurements. There are several methodological limitations that should be considered for this study. Equilibrium was not always achieved in the individual scans, and therefore we used the difference between the MP scans and the control scans for further analyses. Optimally, the control and drug measurements should be made within the same scan. This would need an increase in scan duration in order to attain equilibrium before and after drug administration and requires higher injected activity. In situations of non-equilibrium the estimation of BP may be biased due to effects of ligand distribution or clearance (Carson et al. 1993). In addition, ΔBP may be underestimated if the equilibrium is not established postchallenge (Slifstein et al. 2004). It is currently unknown to what extent these effects may have influenced our results. No MRI scans were made in our study, which would have enabled individual ROI delineation. Unfortunately, this study was not placebo controlled and we did not assess the subjective state during the control condition. Therefore we were unable to distinguish expectation-induced changes in DA from the experience of MP effects. In future studies it is important to control for such variables. In addition, correction for patient 125 [11C]-Raclopride binding in human subjects motion will help to increase the sensitivity of the measurements and coregistration with individual MRI scans would enable partial volume correction. Despite these methodological limitations, our results comply with previous findings, indicating the feasibility of the bolus infusion design combined with a relatively low MP dose to study dopaminergic (dys)function in psychiatric patients. Acknowledgments We gratefully acknowledge Riemer Slart and Sascha Russo for their contribution to the medical screening of the volunteers and Marijtje van Duijn and Vaclav Fidler for their help with the statistical analysis. 126 Chapter 5 References Barrett SP, Boileau I, Okker J, Pihl RO, Dagher A (2004). The hedonic response to cigarette smoking is proportional to dopamine release in the human striatum as measured by positron emission tomography and [11C]raclopride. Synapse 54: 65-71. Berridge KC, RobinsonTE (1998). What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev 28: 309-369. Booij J, Korn P, Linszen DH, van-Royen EA (1997). Assessment of endogenous dopamine release by methylphenidate challenge using iodine-123 iodobenzamide single-photon emission tomography. Eur J Nucl Med 24: 674677. Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de-Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D (1997). Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U-S-A 94: 2569-2574. Camps M, Cortes R, Gueye B, Probst A, Palacios JM (1989). Dopamine receptors in human brain: autoradiographic distribution of D2 sites. Neuroscience 28: 275-290. Carson RE, Channing MA, Blasberg RG, Dunn BB, Cohen RM, Rice KC, Herscovitch P (1993) Comparison of bolus and infusion methods for receptor quantitation: application to [18F]cyclofoxy and positron emission tomography. J Cereb Blood Flow Metab 13: 24-42. Carson RE, Breier A, de-Bartolomeis A, Saunders RC, Su TP, Schmall B, Der MG, Pickar D, Eckelman WC (1997). Quantification of amphetamine-induced changes in [11C]raclopride binding with continuous infusion. J Cereb Blood Flow Metab 17: 437-447. Carson RE (2000). PET physiological measurements using constant infusion. Nucl Med Biol 27: 657-660. De la Fuente Fernandez R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ (2001). Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease. Science 293: 1164-1166. 127 [11C]-Raclopride binding in human subjects De la Fuente Fernandez R, Phillips AG, Zamburlini M, Sossi V, Calne DB, Ruth TJ, Stoessl AJ (2002). Dopamine release in human ventral striatum and expectation of reward. Behav Brain Res 136: 359-363. Dewey SL, Smith GS, Logan J, Brodie JD, Fowler JS, Wolf AP (1993). Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modify synaptic dopamine levels. Synapse 13: 350-356. Di Chiara G, Imperato A (1988). Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA. 85: 5274-5278. Drevets WC, Gautier C, Price JC, Kupfer DJ, Kinahan PE, Grace AA, Price JL, Mathis CA (2001). Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria. Biol Psychiatry 49: 81-96. Ehrin E, Gawell L, Högberg T, de Paulis T, Ström P (1987). Synthesis of 3 11 (methoxy- H)- and (methoxy- C)- labelled raclopride, speccific dopamine D-2 receprtor ligands. J Label Compd Radiopharm 24: 931-939. Hernandez L, Lee F, Hoebel BG (1987). Simultaneous microdialysis and amphetamine infusion in the nucleus accumbens and striatum of freely moving rats: increase in extracellular dopamine and serotonin. Brain Res Bull 19: 623628. Hurd YL, Ungerstedt U (1989). In vivo neurochemical profile of dopamine uptake inhibitors and releasers in rat caudate-putamen. Eur J Pharmacol 166: 251-260. Ikemoto S, Panksepp J (1999). The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to rewardseeking. Brain Res Brain Res Rev 31: 6-41. Ito H, Hietala J, Blomqvist G, Halldin C, Farde L (1998). Comparison of the transient equilibrium and continuous infusion method for quantitative PET analysis of [11C]raclopride binding. J Cereb Blood Flow Metab 18: 941-950. Janowsky DS, Davis JM (1976). Methylphenidate, dextroamphetamine, and levamfetamine. Effects on schizophrenic symptoms. Arch Gen Psychiatry 33: 304-308. Joyce PR, Donald RA, Nicholls MG, Livesey JH, Abbott RM (1986). Endocrine and behavioural responses to methylphenidate in depression. Psychol Med 16: 531-540. Kapur S (2003). Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 160: 13-23. 128 Chapter 5 Kapur S, Mamo D (2003). Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 27: 1081-1090. Kegeles LS, Zea-Ponce Y, Abi-Dargham A, Rodenhiser J, Wang T, Weiss R, Van-Heertum RL, Mann JJ, Laruelle M (1999). Stability of [123I]IBZM SPECT measurement of amphetamine-induced striatal dopamine release in humans. Synapse 31: 302-308. Kuczenski R, Segal DS (1997). Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine. J Neurochem 68: 2032-2037. Kunig G, Leenders KL, Martin-Solch C, Missimer J, Magyar S, Schultz W (2000). Reduced reward processing in the brains of Parkinsonian patients. Neuroreport 11: 3681-3687. Laruelle M, Abi-Dargham A, van-Dyck CH, Rosenblatt W, Zea-Ponce Y, Zoghbi SS, Baldwin RM, Charney DS, Hoffer PB, Kung HF, Innis RB (1995). SPECT imaging of striatal dopamine release after amphetamine challenge. J Nucl Med 36: 1182-1190. Laruelle M, D'Souza CD, Baldwin RM, Abi-Dargham A, Kanes SJ, Fingado CL, Seibyl JP, Zoghbi SS, Bowers MB, Jatlow P, Charney DS, Innis RB (1997). Imaging D2 receptor occupancy by endogenous dopamine in humans. Neuropsychopharmacology 17: 162-174. Laruelle M (2000). Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab 20: 423451. Leenders KL (2002). Disease process and drug treatments in Parkinson's disease. Eur Neuropsychopharmacol 12: 575-580. Leyton M, Boileau I, Benkelfat C, Diksic M, Baker G, Dagher A (2002). Amphetamine-induced increases in extracellular dopamine, drug wanting, and novelty seeking: a PET/[11C]raclopride study in healthy men. Neuropsychopharmacology 27: 1027-1035. Lidow MS, Goldman-Rakic PS, Rakic P, Innis RB (1989). Dopamine D2 receptors in the cerebral cortex: distribution and pharmacological characterization with [3H]raclopride. Proc Natl Acad Sci USA 86: 6412-6416. Marenco S, Carson RE, Berman KF, Herscovitch P, Weinberger DR (2004). Nicotine-induced dopamine release in primates measured with [11C]raclopride PET. Neuropsychopharmacology 29: 259-268. 129 [11C]-Raclopride binding in human subjects Marsteller DA, Gerasimov MR, Schiffer WK, Geiger JM, Barnett CR, Borg JS, Scott S, Ceccarelli J, Volkow ND, Molina PE, Alexoff DL, DeweySL (2002). Acute handling stress modulates methylphenidate-induced catecholamine overflow in the medial prefrontal cortex. Neuropsychopharmacology 27: 163170. Martinez D, Slifstein M, Broft A, Mawlawi O, Hwang DR, Huang Y, Cooper T, Kegeles L, Zarahn E, Abi-Dargham A, Haber SN, Laruelle M (2003). Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamine-induced dopamine release in the functional subdivisions of the striatum. J Cereb Blood Flow Metab 23: 285-300. McClure SM, Laibson DI, Loewenstein G, Cohen JD (2004). Separate neural systems value immediate and delayed monetary rewards. Science 306: 503507. Naranjo CA, Tremblay LK, Busto UE (2001). The role of the brain reward system in depression. Prog Neuropsychopharmacol Biol Psychiatry 25: 781823. Oswald LM, Wong DF, McCaul M, Zhou Y, Kuwabara H, Choi L, Brasic J, Wand GS (2005). Relationships Among Ventral Striatal Dopamine Release, Cortisol Secretion, and Subjective Responses to Amphetamine. Neuropsychopharmacol, to be published. Piccini P, Pavese N, Brooks DJ (2003). Endogenous dopamine release after pharmacological challenges in Parkinson's disease. Ann Neurol 53: 647-653. Pruessner JC, Champagne F, Meaney MJ, Dagher A (2004). Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride. J Neurosci 24: 2825-2831. Rottenberg DA, Moeller JR, Strother SC, Dhawan V, Sergi ML (1991). Effects of percent thresholding on the extraction of [18F]fluorodeoxyglucose positron emission tomographic region-of-interest data. J Cereb Blood Flow Metab 11: A83-88. Schmidt K, Nolte-Zenker B, Patzer J, Bauer M, Schmidt LG, Heinz A (2001). Psychopathological correlates of reduced dopamine receptor sensitivity in depression, schizophrenia, and opiate and alcohol dependence. Pharmacopsychiatry 34: 66-72. Schultz W (1998). Predictive reward signal of dopamine neurons. J Neurophysiol 80: 1-27. Slifstein M, Narendran R, Hwang DR, Sudo Y, Talbot PS, Huang Y, Laruelle M (2004) Effect of amphetamine on [(18)F]fallypride in vivo binding to D(2) 130 Chapter 5 receptors in striatal and extrastriatal regions of the primate brain: Single bolus and bolus plus constant infusion studies. Synapse 54: 46-63. Small DM, Jones-Gotman M, Dagher A (2003). Feeding-induced dopamine release in dorsal striatum correlates with meal pleasantness ratings in healthy human volunteers. Neuroimage 19: 1709-1715. Spanagel R, Weiss F (1999). The dopamine hypothesis of reward: past and current status. Trends Neurosci 22: 521-527. Sun W, Ginovart N, Ko F, Seeman P, Kapur S (2003). In vivo evidence for dopamine-mediated internalization of D2-receptors after amphetamine: differential findings with [3H]raclopride versus [3H]spiperone. Mol Pharmacol 63: 456-462. Tsukada H, Miyasato K, Kakiuchi T, Nishiyama S, Harada N, Domino EF (2002). Comparative effects of methamphetamine and nicotine on the striatal [(11)C]raclopride binding in unanesthetized monkeys. Synapse 45: 207-212. Ungless MA (2004). Dopamine: the salient issue. Trends Neurosci. 27:702-706. Volkow ND, Wang GJ, Fowler JS, Logan J, Schlyer D, Hitzemann R, Lieberman J, Angrist B, Pappas N, MacGregor R, Burr G, Cooper T, Wolf A (1994). Imaging endogenous dopamine competition with [11C]raclopride in the human brain. Synapse 16: 255-262. Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Wong C, Hitzemann R, Pappas NR (1999a). Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors. J Pharmacol Exp Ther 291: 409-415. Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Gifford A, Hitzemann R, Ding YS, Pappas N (1999b). Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels. Am J Psychiatry 156: 1440-1443. Volkow ND, Fowler JS, Wang GJ (2002a). Role of dopamine in drug reinforcement and addiction in humans: results from imaging studies. Behav Pharmacol 13: 355-366. Volkow ND, Wang GJ, Fowler JS, Thanos PP, Logan J, Gatley SJ, Gifford A, Ding YS, Wong C, Pappas N (2002b). Brain DA D2 receptors predict reinforcing effects of stimulants in humans: replication study. Synapse 46: 79-82. Volkow ND, Wang GJ, Fowler JS, Molina PE, Logan J, Gatley SJ, Gifford A, Ding YS, Wong C, Pappas NR, Zhu W, Swanson JM (2003). Cardiovascular effects of methylphenidate in humans are associated with increases of 131 [11C]-Raclopride binding in human subjects dopamine in brain and of epinephrine in plasma. Psychopharmacology (Berl) 166: 264-270. Wang G-J, Volkow ND, Hitzemann RJ, Wong C, Angrist B, Burr G, Pascani K, Pappas N, Lu A, Cooper T, Lieberman JA (1997). Behavioral and cardiovascular effects of intravenous methylphenidate in normal subjects and cocaine abusers. Eur Addict Res 3:49-54. Wise RA (2004). Dopamine, learning and motivation. Nat Rev Neurosci 5: 483494. Zald DH, Boileau I, El-Dearedy W, Gunn R, McGlone F, Dichter GS, Dagher A (2004). Dopamine transmission in the human striatum during monetary reward tasks. J Neurosci 24: 4105-4112. 132